Survival of tumors such as CML are uniquely dependent on the activity of oncogenes that confer a gain of function. Inhibition of the BCR/ABL function by a variety of means has provided voluminous evidence of the requirement of this oncoprotein for tumorigenesis and maintenance of CML. The impressive clinical success of STI571 (Imatinab mesylate) against chronic myelogenous leukemias and acute lymphocytic leukemias expressing this oncoprotein emphasizes the importance of developing therapeutic strategies aimed at this target. However, evaluation of therapeutic outcome has demonstrated that failure to completely inhibit the activity of BCR/ABL kinase may permit resistance. We hypothesize that therapeutic approaches that decrease expression of target oncoproteins that are essential for tumorigenesis will complement the actions of specific enzyme inhibitors. The goals of this project are to validate and implement a sequential blockade strategy that will diminish expression of BCR/ABL. Specifically, we will develop therapeutic strategies to inhibit transcription of the oncogene and translation of its message that will complement the actions of inhibitors of its enzymatic activity. In such a sequential blockade of molecular target synthesis and activity, the biological context of tumorigenesis will provide the basis for specificity, both in cell lines and in primary leukemia cells during translational clinical trials. To achieve these goals, we will investigate the following Specific Aims: * Develop rationales and test proof-of-concept for the sequential blockade strategy to inactivating oncoproteins * Evaluate the sequential blockade strategy in BCR/ABL-expressing primary leukemia cells from patients with CML or ALL * Validate the sequential blockade concept in pharmacodynamically-designed clinical trials